Method of analysing a pharmaceutical sample

ABSTRACT

The present invention relates to a method for analysing the amount of free gas within a pharmaceutical sample. According to the invention the method comprises the following steps: providing a sample before an irradiating source; irradiating the sample with at least one beam of electromagnetic radiation; detecting radiation emitted through the sample and generating signals corresponding to the amount of free gas in the sample, and correlating the generated signals to at least one solid state parameter of the sample.

FIELD OF THE INVENTION

The present invention relates to a method for analysing a pharmaceuticalsample, e.g. a tablet, a granule, an encapsulated pellet, a powder, acapsule, a multiple unit pellet system (MUPS) or a similar sampleforming a pharmaceutical dose or a sub-fraction of a dose.

BACKGROUND OF THE INVENTION

Optical measurements are becoming increasingly important for analysiswithin the pharmaceutical industry. Spectroscopy offers the obviousadvantages of fast, non-destructive, non-invasive and flexible methodswell applicable for analysis near or in the production line. In thiscontext, near-infrared (NIR) spectroscopy is a well-establishedtechnique for qualitative and quantitative analysis of the activecomponent and excipients in many different products. In parallel,spectroscopic techniques for measuring structural parameters ofpharmaceuticals have been developed; in particular light scatteringmethods are well known techniques for determination of particle sizedistribution of powders and solutions. However, determination of physicomechanical parameters of a solid or semi-solid sample is more complexthan analysis of chemical content. In fact, for most such physicalparameters there is a lack of relevant measurement techniques. Forinstance, a dissolution testing of a tablet may show that the activecomponent is released too slowly. However, dissolution testing is atechnique that measures indirect effects of a deviating sample batchrather than probing the physico-mechanical parameters that are theprimary cause of the deviation.

The article “Analysis of gas dispersed in scattering media” from M.Sjöholm et al, Optics Letter, Vol. 26, No.1 describes how free gasdispersed in scattering materials can be detected and characterised byuse of diode laser spectroscopy. Gas detection is made possible by thecontrast of the narrow absorptive feature of free-gas molecules asopposed to the small wavelength dependence of the absorption andscattering cross sections in solids and liquids. This method is,however, capable of providing information only regarding the amount ofgas, i.e. free oxygen contained in the scattering medium.

SUMMARY OF THE INVENTION

It is an aim of the present invention to provide a method for analysinga pharmaceutical sample, which is capable of providing information as toat least one solid state parameter of the sample.

According to a first aspect of the invention there is provided a methodfor analysing the amount of free gas within a pharmaceutical sample.According to the invention the method comprises the following steps:

-   -   providing a sample before an irradiating source,    -   irradiating the sample with at least one beam of electromagnetic        radiation,    -   detecting radiation emitted from the sample and generating        signals corresponding to the amount of free gas in the sample,        and,    -   correlating the generated signals to at least one solid state        parameter of the sample.

By measuring the content of free gas in solid samples, a correlation tosolid state parameters can be achieved. Since the amount of free gas ina sample correlates with the intra particle as well as the interparticlevoid volume of the sample, an indirect quantitative estimation ofspecific solid state parameters can be attained.

A solid state parameter relates to both chemical and physical propertiesof the sample. A pharmaceutical sample consists of a raw material or ofa compressed or uncompressed blend of pharmaceutical raw materials. Byanalysing the sample, information about its chemical as well as itsphysical parameters may be attained. The meaning of chemical parametersis concentrations of the different components and their distributionwithin the sample, such as the content of the active substance in atablet. By physical parameters, on the other hand, is meant thestructure, the distribution, the size, the form, the density, themorphology of a sample, particles within the sample, or cavities withinthe sample. It can also be parameters related to dynamic properties suchas heat conduction or gas diffusion within the sample. Thus, the solidstate parameters can be divided into static and dynamic solid stateparameters.

For example, the solid state parameter may represent the diffusitivityof a gas in a sample, the hardness of a sample, the disintegrationability of a sample, the dissolution ability of a sample, thecompressibility of a sample, the aggregation properties of the sample orthe flowability of a sample.

One way of performing this measurement is to use an absorptiontechnique, such as wavelength modulation spectroscopy. The wavelength ofa light source, preferably a diode laser, is scanned in time such thatthe wavelength is shifted back and forth across a narrow wavelengthregion, which includes the absorption wavelength of the free gas to bedetected. If the scattering medium contains free gas molecules, thesewill absorb the radiation in a very narrow wavelength region, givingrise to a tiny, but sharp absorption feature in the intensity of therecorded diffusely scattered light. According to the present inventionthe free gas is preferably oxygen, carbondioxide or water vapour.

In order to increase the detection sensitivity a modulation current ofhigh frequency is superimposed on the drive current to the diode laserand the detector signal is picked up phase-sensitively by a lock-inamplifier. The resulting wavelength modulation signal is typicallyseveral orders of magnitude larger than that of direct absorption. Ifthe detection is performed at the same frequency or at some harmonic avery sensitive detection is reached. This arrangement can be performedin transmission mode or in reflection mode depending on how the detectoris oriented in relation to the light delivery system. Thus, theradiation emitted from the sample may comprise transmitted radiation aswell as reflected radiation.

In a first embodiment, the radiation irradiating the sample comprisesinfrared radiation. Preferably, the infrared radiation is in the nearinfrared (NIR) spectral region.

More preferably, the radiation has a frequency in the rangecorresponding to wavelengths of from about 700 to about 2100 nm,particularly from 700 to 1300 nm.

In another embodiment the radiation irradiating the sample comprisesvisible light.

In still another embodiment the radiation irradiating the samplecomprises UV radiation.

The sample to be analysed is a pharmaceutical sample, preferably a solidsample and in particular a tablet, a granule, an encapsulated pellet, acapsule, a bulk powder or an equivalent pharmaceutical dose or fractionof a dose.

Using optical methods for the measurement of free gas in a sample, i.e.air gives several advantages over traditional methods. First, for solidturbid media the light scatters around inside samples in such a way thatthe entire sample volume is measured. Secondly, optical methods can beused for both large air cavities and for extremely small air microcavities. Thirdly, using spectroscopic methods fast measurementsdirectly in the production line is possible, either at-line, on-line orin-line. This can be used to generate data for feedback to control theprocess to obtain precise predetermined product characteristics.Further, this can also be performed at multiple stages within theproduction line so that not only the end product, such as tablets, ischaracterised but also raw materials, powders, pellets or granules canbe characterised. The latter characterisation can provide an indicatorfor the success of the following production steps such as tabletting.

The technique of measuring sample gas concentrations with opticalspectroscopy and relating that to physical properties of the sample canbe used in several manufacturing steps of pharmaceuticals. By measuringthe amount of dispersed gas in tablets an indirect correlation to tablethardness can be reached. This is based on the assumption that the moremicro cavities within the sample the higher is the probability of acrack to develop in the tablet.

Measurements of certain solid state parameters, for example tablethardness are a requirement in manufacturing of pharmaceutical tablets.The tablet hardness in turn affects tablets disintegration propertiesand release of the active substance in vivo. Hardness measurements areconventionally performed by applying a mechanical force across thetablet by means of two metal legs. As the mechanical force is graduallyincreased, the tablet breaks at a certain force, which provides areading of the tablet hardness. This analysis suffers from poor accuracyand precision due to inherent in-homogeneities and microscopic crackswithin tablets. In addition, conventional methods for assessing hardnessapplies the mechanical force in different ways, for example usingconstant speed or constant force. Thereby different results are obtainedfor the sample. Furthermore, the analysis requires that tablets aresampled from a production stream and analysed off-line. An opticalmethod, on the other hand, is in general both fast and can be appliedwithin the production line and can also be fairly accurate.

Tablet hardness can according to this invention be related to the amountof encapsulated air within tablets. The harder the tablet matrix ispressed together, the lower amount of air will reside in the tablet. Theamount of air within a turbid medium can be determined by measuring thecontent of molecular oxygen in the sample. Since normal air containsabout 21% oxygen, the oxygen measurement may give an indirectquantitative estimation of the tablet hardness.

Measurements performed according to the invention on powders, granulesor pellets during or after compression can be used to assess theviscoelastic characteristics of pharmaceutical compacts. For example, bycomparing the difference in molecular oxygen in the pharmnaceuticalcompact during compression with that after decompression deformationproperties or elasticity of a sample can be monitored.

In another embodiment of the invention the measurement is performed onwater vapour rather than on oxygen. By measuring the water vapourcontent of samples a correlation to the contained moisture within thesample can be attained.

Yet another application is where the invention is used for powdermeasurements to assess the structure of agglomerates. In this way theirbulk properties such as deformation and fracture can be predicted.Because the invention can be applied in situ, for example by conductingmeasurements in a process vessel, precise control can be obtained inunit operations such as granulation, drying, compaction and transport.

Another application for the present invention is prediction ofdisintegration/dissolution testing. Pharmaceutical tablets are testedfor their dissolution properties in a liquid medium. The conventionalrational include putting the tablets in glass vessels filled with heateddissolution medium under agitation of paddles and sampling aliquots ofthe solution at pre-determined times. The time of an analysis typicallyranges between 15 minutes to 24 hours. There is a correlation betweenthe dissolution properties of a sample and its degree of packing, whichin turn can be measured with diode laser spectroscopy using the claimedmethod.

As spectroscopic techniques are fairly fast, dynamic events can bemonitored. One such mechanism is diffusion through solid samples. Somepharmaceutical solids, in particular pellets, are built from sub-layers,each layer having a particular property. As an example, anacid-resistant film may be the outer coating on pellets to prevent thepellets from disintegrate already in the upper part of the stomach.Diode laser spectroscopy offers an alternative method of estimatingdiffusion across coatings. This can be done by preconditioning samplesin a nitrogen atmosphere and recording the subsequent diffusion ofoxygen into the sample after placing them in normal atmosphere again.The amount of free gas within the sample as a function of time measuredby diode laser spectroscopy is correlated with the dynamics of oxygendiffusion. Alternatively the experiment is performed in reversed orderstarting from a normal atmosphere and following the diffusive exchangeof oxygen with nitrogen within the sample.

Physico-mechanical properties of powders may also be assessed by dynamicmeasurements. A signature of the powders dynamics regarding flowabilityand packing can be obtained from monitoring a series of consecutivemeasurements where the sample particles are rearranged continuously bytumbling, mixing or any other particle motion.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the equipment to carry out the method according tothe invention.

FIGS. 2 a-c show three raw spectra illustrating the oxygen concentrationin a sample wherein the light absorption is shown as a function offrequency for a) a blank sample; b) a sample from a first batch, and c)a sample from a second batch.

FIG. 3 illustrates the hardness of a number of samples from twodifferent batches, batch A and batch B, as a function of lightabsorption.

FIG. 4 illustrates the equipment to carry out measurements according tothe invention during compaction of powders, i.e. a tabletting process.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

One way of performing the measurement according to the present inventionis to use an absorption technique, such as wavelength modulationspectroscopy. With this technique the wavelength of a light source, inthis case a diode laser is scanned in time such that the wavelength isshifted back and forth across a small wavelength region, which includesthe absorption wavelength of a free gas, i.e. oxygen. The diode laser isfurthermore modulated at a high frequency and a very sensitive detectionat the same frequency or at some harmonic, referred to as lock-indetection, is reached. This arrangement can be performed in atransmission mode or in reflection mode depending on how the detector isoriented in relation to the light delivery system.

The measurements of free gas content can be realised in different ways.The use of wavelength modulation diode laser spectroscopy is convenientbecause of the small size and low cost of these lasers. Together withlock-in technique it constitutes a compact and robust system. Bothreflectance and transmission geometries can be employed. Theexperimental set-up used to prove the concept of tablet hardnessmeasurements with transmission-mode wavelength modulation spectroscopyis shown in FIG. 1. A tunable diode laser 2 with a nominal wavelength of757 nm together with a focusing lens 4 was positioned inside a chamber6. The chamber was flushed with nitrogen gas to avoid extra oxygenwithin the optical path. The diode laser was 2 controlled by a laserdriver 8 and the wavelength was tuned by applying a current ramp at 4Hz. The drive current for the diode laser was mixed with a 55 kHzsinusoidal current component for lock-in amplification. The output lightof the diode laser was guided through an optical fibre 10 and collimatedby a collimator 12 before being directed to the sample 14. Also the airgap between the distal end of the fibre 10 and the collimator lens wasflushed with nitrogen gas. As an alterative, the sample holder (notshown) can be designed to minimise the optical path length through openair, making the nitrogen flow unnecessary. The light transmitted throughthe sample 14 was collected by a detector 16, in this case a photomultiplier with an optical cut-off filter 18 in front to remove lightthat did not originate from the laser and was not transmitted throughthe sample. The signal from the photo multiplier was fed to a lock-inamplifier 20 for phase-sensitive detection of the transmitted light. Theextracted second-harmonic component and the direct signal from the photomultiplier 16 were accumulated in a digital oscilloscope 22.

The sample 14 was placed in a sample holder (not shown) between thecollimator 12 and the detector 16 for measurements to mask off any straylight not going through the sample. Several samples were measured andafter that the tablet hardness was measured with a conventionalinstrument. A blank spectrum of an empty sample holder was measured forcomparison. For the first sample the signal was measured for severalcollimator-detector distances and the standard-addition approach wasutilised to achieve absolute measures of the amount of oxygen within thedetection path.

FIGS. 2 a-2 c show raw spectra of the oxygen concentration in a sampleas a function of frequency. FIG. 2 a is an example of wavelengthmodulation signals of a blank (no sample), and FIG. 2 b and 2 c showsignals from two different samples, i.e: tablets from batch A and batchB respectively. The oxygen peak for each sample can be seen atapproximately the frequency 0.1 in arbitrary units (a.u.).

In FIG. 3, a correlation plot for a number of tablets from the twodifferent batches, batch A and batch B, shows the tablet hardness (kP)measured with a conventional method as a function of the absorptionsignal (a.u.) measured with the new method. As can be seen there is acorrelation between the conventional and the novel measuring technique.

In FIG. 4 is shown an example where the invention and measurement systemdescribed in FIG. 1 is applied to monitor changes in a bulk powdersample 14 during compaction. The light guides 10 are here arranged toilluminate the sample within the compaction equipment comprising a die28 and a punch 30. This measurement can be performed in situ in atabletting machine, thereby enabling in-line measurements in themanufacturing process. This can also be performed in a test systemat-line from the process. In both cases, generated data can be used topredict physico-mechanical properties of the samples that can be used asfeedback control data in the process to obtain predetermined productcharacteristics.

1. A method for analysing the amount of free gas within a pharmaceuticalsample, the method comprising the steps of: a) providing a sample beforean irradiating source; b) irradiating the sample with at least one beamof electromagnetic radiation; c) detecting radiation emitted from thesample; d) generating signals corresponding to the amount of free gas inthe sample; and, e) correlating the generated signals to at least onesolid state parameter of the sample.
 2. The method according to claim 1,wherein the emitted radiation comprises transmitted radiation from thesample.
 3. The method according to claim 1, wherein the emittedradiation comprises reflected radiation from the sample.
 4. The methodaccording to claim 1, wherein the emitted radiation comprisestransmitted radiation and reflected radiation from the sample.
 5. Themethod according to claim 1, wherein the free gas is oxygen.
 6. Themethod according to claim 1, wherein the free gas is carbon dioxide. 7.The method according to claim 1, wherein the free gas is water vapour.8. The method according to claim 1, further comprising the step ofdetecting radiation emitted as a function of time.
 9. The methodaccording to claim 1, wherein the solid state parameter represents thehardness of the sample.
 10. The method according to claim 1, wherein thesolid state parameter represents the disintegrability of the sample. 11.The method according to claim 1, wherein the solid state parameterrepresents the dissolvability of the sample.
 12. The method according toclaim 1, wherein the solid state parameter represents the flowability ofthe sample.
 13. The method according to claim 1, wherein the solid stateparameter represents the aggregation properties of the sample.
 14. Themethod according to claim 1, wherein the solid state parameterrepresents the density of the sample.
 15. The method according to claim1, wherein the pharmaceutical sample is a solid sample.
 16. The methodaccording to claim 15, wherein the pharmaceutical sample is positionedinside a blister of a blister pack.
 17. The method according to claim 1,wherein the radiation irradiating the sample comprises infrared (IR)radiation.
 18. The method according to claim 17, wherein the IRradiation is near infrared (NIR) radiation.
 19. The method according toclaim 1, wherein the radiation has a wavelength in the range of fromabout 700 to about 2100 nm.
 20. The method according to claim 1, whereinthe radiation irradiating the sample comprises visible light.
 21. Themethod according to claim 1, wherein the radiation irradiating thesample comprises UV radiation.
 22. The method according to claim 1,wherein the irradiating source comprises a diode laser.
 23. The methodaccording to claim 1, wherein the emitted radiation is detected by aphoto multiplier.
 24. The method according to claim 1, wherein theemitted radiation is detected by a photo diode.
 25. The method accordingto claim 1, wherein the analysis is conducted in a manufacturing areaat-line.
 26. The method according to claim 1, wherein the analysis isconducted in a manufacturing area on-line.
 27. The method according toclaim 1, wherein the analysis is conducted in-line in a manufacturingprocess vessel.
 28. The method according to claim 1, wherein the amountof free gas analysed within the pharmaceutical sample is used asfeedback control data in a manufacturing process in order to obtainpredetermined physico-mechanical characteristics of the pharmaceuticalsample.
 29. The method according to claim 1, wherein the solid stateparameter represents the diffusitivity of a gas in a sample.
 30. Themethod according to claim 15, wherein the solid sample is selected fromthe group consisting of a tablet, a granule, a capsule, a bulk powder, apharmaceutical dose, and a pharmaceutical dosage form.
 31. The methodaccording to claim 19, wherein the radiation has a wavelength in therange of from about 700 to about 1300 nm.
 32. The method according toclaim 1, wherein the generated signals are correlated to more than onesolid state parameter of the sample.